Truncation of Notch1 has been shown to cause a subtype of acute leukemia1, and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice2. Here we identify a new mechanism for disrupting Notch signaling in human tumorigenesis, characterized by altered function of a new ortholog of the Drosophila melanogaster Notch co-activator molecule Mastermind. We cloned the t(11;19) translocation that underlies the most common type of human malignant salivary gland tumor. This rearrangement fuses exon 1 from a novel gene of unknown function at 19p13, termed mucoepidermoid carcinoma translocated 1 (MECT1), with exons 2–5 of a novel member of the Mastermind-like gene family (MAML2) at 11q21 (ref. 3). Similar to D. melanogaster Mastermind and MAML1 (refs. 4,5), full-length MAML2 functioned as a CSL (CBF-1, suppressor of hairless and Lag-1)-dependent transcriptional co-activator for ligand-stimulated Notch. In contrast, MECT1–MAML2 activated transcription of the Notch target gene HES1 independently of both Notch ligand and CSL binding sites. MECT1–MAML2 induced foci formation in RK3E epithelial cells, confirming a biological effect for the fusion product. These data suggest a new mechanism to disrupt the function of a Notch co-activator in a common type of malignant salivary gland tumor.
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We are grateful to M. Kuehl, P. Aplan and T. Ried for helpful suggestions; P. Gao and J. Liu for their help; B. Baum for providing the HSY cells; M. Wolfe for providing the γ-secretase inhibitor; and A. Capobianco for advice on the RK3E assay. We acknowledge partial support by an American Society of Hematology Scholar Award and a General Motors Cancer Research Scholar Award (L.W.).
A patent application has been filed (by F.J.K. and G.T.) for the molecular diagnosis of mucoepidermoid carcinoma.
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Tonon, G., Modi, S., Wu, L. et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33, 208–213 (2003). https://doi.org/10.1038/ng1083
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